Further, the transcriptional decreasing effect of intermediate repeat lengths and small deletions in the 3' flanking sequence could probably explain the observed nominally significant association of intermediate repeat alleles and indels in the 3' flanking sequence with increased disease risk in the Belgian ALS and FTLD–ALS population, possibly through subtle changes in C9orf72 expression.
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The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter.
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In HEK293T cells, we observed a highly significant decrease of transcriptional activity of promoter fragment 1, containing G 4 C 2 repeat alleles with intermediate length within the normal range (9, 14, 19 and 24 units) or within the size range of unclear pathogenicity (31 and 38 units), compared with the normal reference allele with two repeat units ( P <0.0001; Figure 5a ).
Only one study found a marginally significant association of hypermethylation with shorter repeat size in blood only. 15 Further investigation and replication studies of age at onset and methylation correlations with repeat size in large cohorts are needed.